Clinical Trials /

Safety and Efficacy of OT-82 in Participants With Relapsed or Refractory Lymphoma

NCT03921879

Description:

This research study will test OT-82, which is an investigational ("research" or "experimental" ) drug. The study has two stages (Stage 1 and Stage 2). The purpose of Stage 1 is to determine the safety and tolerability and the maximum tolerated dose (MTD) or the maximum tested dose of OT-82 administered orally to participants. The purpose of Stage 2 is to determine the preliminary efficacy of OT-82 in relapsed or refractory lymphoma at the MTD or the maximum tested dose. Both parts of the study will also evaluate the pharmacokinetics (absorption, distribution, metabolism, elimination) of OT-82. OT-82 treatment slowed the growth, reduced the size, or in some cases cured certain cancers in animal studies. It is hoped that participants with relapsed or refractory lymphoma treated with OT - 82 in this study will experience slowing tumor growth and/or reduction of tumor size.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Follicular T-Cell Lymphoma
  • Hodgkin Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Primary Mediastinal B-Cell Lymphoma
  • Small Lymphocytic Lymphoma
  • T-Cell Non-Hodgkin Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy of OT-82 in Participants With Relapsed or Refractory Lymphoma
  • Official Title: A Phase 1 Study of OT-82 in Patients With Relapsed or Refractory Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: OT-82-001
  • NCT ID: NCT03921879

Conditions

  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoma, B-Cell
  • Lymphoma, T-Cell
  • Lymphoma, Follicular
  • Lymphoma, Peripheral T-Cell
  • Lymphoma, Hodgkin

Interventions

DrugSynonymsArms
OT-82 Dose EscalationStage 1 Dose Escalation
OT-82 Dose ExpansionStage 2 Dose Expansion

Purpose

This research study will test OT-82, which is an investigational ("research" or "experimental" ) drug. The study has two stages (Stage 1 and Stage 2). The purpose of Stage 1 is to determine the safety and tolerability and the maximum tolerated dose (MTD) or the maximum tested dose of OT-82 administered orally to participants. The purpose of Stage 2 is to determine the preliminary efficacy of OT-82 in relapsed or refractory lymphoma at the MTD or the maximum tested dose. Both parts of the study will also evaluate the pharmacokinetics (absorption, distribution, metabolism, elimination) of OT-82. OT-82 treatment slowed the growth, reduced the size, or in some cases cured certain cancers in animal studies. It is hoped that participants with relapsed or refractory lymphoma treated with OT - 82 in this study will experience slowing tumor growth and/or reduction of tumor size.

Detailed Description

      OT-82 affects an enzyme in the cancer cell called nicotinamide phosphoribosyltransferase
      (abbreviated NAMPT), which is involved with making energy for the cancer cell. OT-82 deprives
      the cancer cell of the energy that it needs to grow and divide.

      This is a Phase 1, non-randomized (all participants will receive the study medication),
      open-label (identity of the study drug will be known to the participant and the study staff),
      controlled (the methods of the study are not random) study. Approximately 45 -50 participants
      at approximately 10 study centers across the USA will take part in this research study. The
      starting dose for Stage 1 is 16.5 mg/m2 per day. Participants in Stage 1 will be assigned a
      dose dependent on when he or she entered the study. Doses will increase for each new group of
      3 to 6 participants until the maximum tolerated dose (MTD) or the maximum tested dose is
      reached. OT-82 is an oral liquid suspension that will be taken by mouth once per day for 3
      days followed by a 4-day rest period.. A participant may continue to receive treatment with
      OT-82 as long as the study doctor feels it is in their best interest; as long as the
      participant does not develop intolerable side effects; as long as the participant wishes to
      remain in the study; or as long as the sponsor does not close the study.

      Participants in Stage 2 of the study will receive either the MTD or the maximum tested dose
      of OT-82 determined in Stage 1. Assessment of anti-tumor activity will primarily focus on
      categorical objective response (Partial Response (PR) or Complete Response (CR)) as defined
      according to the consensus recommendations of the Lugano Classification criteria for
      malignant lymphoma (Cheson et al., 2014).
    

Trial Arms

NameTypeDescriptionInterventions
Stage 1 Dose EscalationExperimentalThe dose escalation arm will use a modified 3+3 design to determine the maximum tolerated dose. or maximum tested dose.
  • OT-82 Dose Escalation
Stage 2 Dose ExpansionExperimentalThe dose expansion arm will use the maximum tolerated dose to determine preliminary efficacy.
  • OT-82 Dose Expansion

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years.

          -  Provides signed informed consent before initiation of any study-specific procedures or
             treatment.

          -  Histologically (tumor tissue) confirmed diagnosis of lymphoma that has progressed
             despite prior treatment, and for which additional options leading to meaningful
             clinical benefit are not available. Lymphoma diagnoses may include the following:

             a. Confirmed histological diagnosis of the following types of B-cell Non-Hodgkin
             lymphoma (NHL): i. Low-grade B-cell NHLs including, but not limited to, FL, MCL, MZL,
             PMBL, LPC, or CLL/SLL. ii. Intermediate to high grade B-cell NHLs including, but not
             limited to DLBCL and other intermediate grade B-cell NHL, with disease progression
             following stem cell transplant or patient must be unwilling, unable or not an
             appropriate candidate for such. iii. Transformed Follicular Lymphoma. b. PTCL and
             others T-cell lymphoma, in which there is measurable non-cutaneous disease.

             c. Hodgkin's Lymphoma

          -  Measurable disease in all lymphoma classes except PTCL.

               1. Defined as nodal lesions >1.5 cm or extra-nodal, non-cutaneous lesions > 1.0 cm.

               2. Target lesions that have been previously irradiated and have not progressed since
                  radiation are not considered measurable.

               3. Patients with PTCL may be eligible if they do not have measurable disease if they
                  have skin disease.

          -  ECOG performance status of 0 or 1. This is a measure of a participant's ability to
             manage self care, mobility, work status, and other measures.

          -  Adequate baseline organ function.

          -  Adequate baseline hematologic (blood) function.

          -  Negative blood pregnancy test result obtained during screening if the patient is
             sexually mature woman who has not undergone a hysterectomy or ovary removal or has not
             been naturally postmenopausal for at least 24 consecutive months.

          -  Participant agrees to use acceptable contraceptive methods for the duration of time on
             the study, and continue to use acceptable contraceptive methods for 3 months after the
             last treatment with OT-82:

          -  Participant agrees to, and be capable of, adhering to the study visit schedule and
             other protocol requirements, including follow-up for survival.

        Exclusion Criteria:

          -  Persistent clinically significant toxicities from previous anticancer therapy
             (excluding alopecia, which is permitted, and excluding Grades 2 and 3 laboratory
             abnormalities if they are not associated with symptoms, are not considered clinically
             significant by the Investigator, and can be managed with available medical therapies).

          -  Treatment with cytotoxic, biologic, or targeted therapies for lymphoma within 14 days
             before administration of the patient's first dose of OT-82.

          -  Treatment with an investigational drug within 28 days before administration of the
             patient's first dose of OT-82.

          -  Treatment with a stem cell transplant with an infusion of stem cells no less than 8
             weeks before administration of the patient's first dose of OT-82. There should be no
             graft versus host disease > Grade 1 and participant should have discontinued all
             immunosuppressive therapy for such ≥ 2 weeks from OT-82 treatment.

          -  Radiation therapy within 14 days before administration of the patient's first dose of
             OT-82.

          -  Major surgical procedure within 28 days before administration of the patient's first
             dose of OT-82.

          -  Physical abnormality or medical condition that limits swallowing oral solutions,
             and/or has a history of non-adherence to oral therapies.

          -  Clinically significant gastrointestinal disorder that may alter absorption such as
             malabsorption syndrome or major resection of the stomach or bowels

          -  Additional active malignancy that may confound the assessment of the study endpoints.
             If the participant has a past cancer history (i.e. active malignancy within 2 years
             before study entry) with substantial potential for recurrence, this must be discussed
             with the Sponsor before study enrollment. Patients with the following concomitant
             neoplastic diagnoses are eligible: nonmelanoma skin cancer and carcinoma in situ
             (including transitional cell carcinoma, cervical cancer, anal carcinoma, and melanoma
             in situ).

          -  Breastfeeding.

          -  Clinically significant cardiovascular disease including, but not limited to:

               1. Uncontrolled or any New York Heart Association Class III or IV congestive heart
                  failure.

               2. Uncontrolled angina, history of myocardial infarction, unstable angina, or stroke
                  within 6 months before study entry.

          -  Systolic blood pressure > 170 mm Hg or diastolic blood pressure > 110 mm Hg, or
             clinically significant arrhythmias not controlled by medication.

          -  Average QTc interval by QTcF on triplicate ECGs at screening or baseline > 470 msec
             (females) or > 450 msec (male).

          -  History of additional risk factors for a cardiac condition known as torsade de pointes
             (e.g., heart failure, low potassium, family history of long QT syndrome, use of
             concomitant medications that prolong the cardiac QT/QTc interval).

          -  Uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive
             pulmonary disease, pulmonary hypertension) that, in the opinion of the Investigator,
             would put the patient at significant risk for pulmonary complications during the study
             (patient must not be dependent on oxygen).

          -  History of brain or leptomeningeal malignant disease (CNS imaging is not required
             before study entry unless there is a clinical suspicion of CNS involvement).

          -  Primary CNS lymphoma.

          -  Condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalents) or other immunosuppressive medications within 14 days before
             administration of the patient's first dose of OT-82. Inhaled or topical steroids and
             adrenal replacement doses ≤ 10 mg daily prednisone equivalents are permitted in the
             absence of active autoimmune disease.

          -  Uncontrolled illness including, but not limited to, uncontrolled infection,
             disseminated intravascular coagulation, or psychiatric illness/social situations that
             would limit compliance with study requirements.

          -  Known positive status for HIV and:

               1. Not receiving optimal anti-HIV therapy

               2. Demonstrated to be noncompliant with anti-HIV therapy.

               3. Has evidence of worsening HIV viral load (as assessed by HIV real-time qPCR).

               4. Not willing to attend HIV clinic follow-up at appropriate intervals.

          -  Active or chronic hepatitis B or hepatitis C (screening is not required).

          -  Any medical condition that, in the opinion of the Investigator, places the patient at
             unacceptably high risk for toxicity.

          -  Anticoagulation with warfarin or a direct thrombin inhibitor; a washout period of 7
             days before administration of a patient's first dose of study drug is required for
             patients who are taken off these treatments (treatment with low molecular weight
             heparin is allowed).

          -  Requires a medication(s) that is a strong inhibitor of cytochrome CYP3A4
             (boceprevir,clarithromycin, cobicistat, conivaptan, diltiazem, anoprevir/ritonavir,
             elvitegravir/ritonavir, grapefruit juice, idelasib, indinavir/ritonavir, itraconazole,
             ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir,
             paritaprevir/ritonavir/ombitasvir and/or dasabuvir, posaconazole, ritonavir,
             saquinavir/ritonavir, tipranavir/ritonavir, troleandomycin, voriconazole, and
             telithromycin).

          -  Requires a medication(s) that is a strong inducer of CYP3A4 (carbamazepine,
             enzalutamide, mitotane, phenytoin, rifampin, and St John's wort).

          -  Requires a medication(s) that is a strong inhibitor of P-glycoprotein (P-gp)
             (amiodarone, carvedilol, clarithromycin, cyclosporine, dronedarone, elacridar,
             itraconazole, ketoconazole, lapatinib, lopinavir/ritonavir, propafenone, quinidine,
             ranolazine, reserpine, ritonavir, saquinavir/ritonavir, tacrolimus, telaprevir,
             tipranavir/ritonavir, verapamil).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Occurence of Dose Limiting Toxicities (DLT) in all participants during the Stage 1 Dose Escalation period
Time Frame:C1 (Days 1-28) through study completion.
Safety Issue:
Description:A DLT is a defined Adverse Events (AE) that limits the dosing schedule occurring during Cycle 1 regardless of Investigator attribution to OT-82.

Secondary Outcome Measures

Measure:Evaluate the Maximum Plasma Concentration (Cmax) of OT-82 in Human Participants
Time Frame:Stage 1: Days 1,2,3,4,5,8,15,22, and 29; Stage 2: Days 1,2,8, and 15
Safety Issue:
Description:Blood samples taken prior to administration of the OT-82 dose will be assessed to determine the Cmax of OT-82 in human participants
Measure:Evaluate Time to Maximum Concentration (Tmax) of OT-82 in Human Participants
Time Frame:Stage 1: Days 1,2,3,4,5,8,15,22, and 29; Stage 2: Days 1,2,8, and 15
Safety Issue:
Description:Blood samples taken prior to administration of the OT-82 dose will be assessed to determine the Cmax of OT-82 in human participants
Measure:Evaluate the Area Under the Curve (AUC) of OT-82 in Human Participants
Time Frame:Stage 1: Days 1,2,3,4,5,8,15,22, and 29; Stage 2: Days 1,2,8, and 15
Safety Issue:
Description:Blood samples taken prior to administration of the OT-82 dose will be assessed to determine the AUC of OT-82 in human participants
Measure:Evaluate the Clearance (Cl) of OT-82 in Human Participants
Time Frame:Stage 1: Days 1,2,3,4,5,8,15,22, and 29; Stage 2: Days 1,2,8, and 15
Safety Issue:
Description:Blood samples taken prior to administration of the OT-82 dose will be assessed to determine the Clearance of OT-82 in human participants
Measure:Evaluate Visfatin Levels in Participants treated with OT-82
Time Frame:Stage 1: Days 1,2,3,4,5,8,15,22, and 29; Stage 2: Days 1,2,8, and 15
Safety Issue:
Description:Visfatin, an enzyme involved in the mechanism of OT-82, will be measured with blood samples.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Oncotartis, Inc.

Last Updated

January 23, 2020